• Login
    View Item 
    •   Home
    • UMass Chan Faculty and Staff Research and Publications
    • UMass Chan Faculty and Researcher Publications
    • View Item
    •   Home
    • UMass Chan Faculty and Staff Research and Publications
    • UMass Chan Faculty and Researcher Publications
    • View Item
    JavaScript is disabled for your browser. Some features of this site may not work without it.

    Browse

    All of eScholarship@UMassChanCommunitiesPublication DateAuthorsUMass Chan AffiliationsTitlesDocument TypesKeywordsThis CollectionPublication DateAuthorsUMass Chan AffiliationsTitlesDocument TypesKeywordsProfilesView

    My Account

    LoginRegister

    Help

    AboutSubmission GuidelinesData Deposit PolicySearchingAccessibilityTerms of UseWebsite Migration FAQ

    Statistics

    Most Popular ItemsStatistics by CountryMost Popular Authors

    Combined experimental and computational analysis of DNA damage signaling reveals context-dependent roles for Erk in apoptosis and G1/S arrest after genotoxic stress

    • CSV
    • RefMan
    • EndNote
    • BibTex
    • RefWorks
    Thumbnail
    Name:
    MSB_568.full.pdf
    Size:
    819.2Kb
    Format:
    PDF
    Download
    Authors
    Tentner, Andrea R.
    Lee, Michael J.
    Ostheimer, Gerry J.
    Samson, Leona D.
    Lauffenburger, Douglas A.
    Yaffe, Michael B.
    UMass Chan Affiliations
    Program in Systems Biology
    Document Type
    Journal Article
    Publication Date
    2012-01-31
    Keywords
    Apoptosis
    Cellular Microenvironment
    Computational Biology
    DNA Damage
    Extracellular Signal-Regulated MAP Kinases
    G1 Phase Cell Cycle Checkpoints
    Humans
    Models, Biological
    Models, Theoretical
    Signal Transduction
    Stress, Physiological
    Systems Biology
    Tumor Cells, Cultured
    Validation Studies as Topic
    Apoptosis
    Cell‐Cycle Checkpoint
    DNA Damage
    Erk
    Signal Transduction
    Biochemistry
    Cell Biology
    Computational Biology
    Molecular Biology
    Systems Biology
    Show allShow less
    
    Metadata
    Show full item record
    Abstract
    Following DNA damage, cells display complex multi-pathway signaling dynamics that connect cell-cycle arrest and DNA repair in G1, S, or G2/M phase with phenotypic fate decisions made between survival, cell-cycle re-entry and proliferation, permanent cell-cycle arrest, or cell death. How these phenotypic fate decisions are determined remains poorly understood, but must derive from integrating genotoxic stress signals together with inputs from the local microenvironment. To investigate this in a systematic manner, we undertook a quantitative time-resolved cell signaling and phenotypic response study in U2OS cells receiving doxorubicin-induced DNA damage in the presence or absence of TNFalpha co-treatment; we measured key nodes in a broad set of DNA damage signal transduction pathways along with apoptotic death and cell-cycle regulatory responses. Two relational modeling approaches were then used to identify network-level relationships between signals and cell phenotypic events: a partial least squares regression approach and a complementary new technique which we term 'time-interval stepwise regression.' Taken together, the results from these analysis methods revealed complex, cytokine-modulated inter-relationships among multiple signaling pathways following DNA damage, and identified an unexpected context-dependent role for Erk in both G1/S arrest and apoptotic cell death following treatment with this commonly used clinical chemotherapeutic drug.
    Source
    Tentner AR, Lee MJ, Ostheimer GJ, Samson LD, Lauffenburger DA, Yaffe MB. Combined experimental and computational analysis of DNA damage signaling reveals context-dependent roles for Erk in apoptosis and G1/S arrest after genotoxic stress. Mol Syst Biol. 2012 Jan 31;8:568. doi: 10.1038/msb.2012.1. Link to article on publisher's site
    DOI
    10.1038/msb.2012.1
    Permanent Link to this Item
    http://hdl.handle.net/20.500.14038/49922
    PubMed ID
    22294094
    Notes

    At the time of publication, Michael J. Lee was not yet affiliated with the University of Massachusetts Medical School.

    Related Resources
    Link to Article in PubMed
    Rights

    Copyright 2012 EMBO and Macmillan Publishers Limited

    Molecular Systems Biology is an open-access journal published by European Molecular Biology Organization and Nature Publishing Group. This work is licensed under a Creative Commons Attribution-Noncommercial-Share Alike 3.0 Unported License.

    ae974a485f413a2113503eed53cd6c53
    10.1038/msb.2012.1
    Scopus Count
    Collections
    UMass Chan Faculty and Researcher Publications

    entitlement

    Related items

    Showing items related by title, author, creator and subject.

    • Thumbnail

      Mapping and analysis of Caenorhabditis elegans transcription factor sequence specificities

      Narasimhan, Kamesh; Lambert, Samuel A.; Yang, Ally; Riddell, Jeremy; Mnaimneh, Sanie; Zheng, Hong; Albu, Mihai; Najafabadi, Hamed S.; Reece-Hoyes, John S.; Fuxman Bass, Juan; et al. (2015-04-23)
      Caenorhabditis elegans is a powerful model for studying gene regulation, as it has a compact genome and a wealth of genomic tools. However, identification of regulatory elements has been limited, as DNA-binding motifs are known for only 71 of the estimated 763 sequence-specific transcription factors (TFs). To address this problem, we performed protein binding microarray experiments on representatives of canonical TF families in C. elegans, obtaining motifs for 129 TFs. Additionally, we predict motifs for many TFs that have DNA-binding domains similar to those already characterized, increasing coverage of binding specificities to 292 C. elegans TFs (~40%). These data highlight the diversification of binding motifs for the nuclear hormone receptor and C2H2 zinc finger families, and reveal unexpected diversity of motifs for T-box and DM families. Motif enrichment in promoters of functionally related genes is consistent with known biology, and also identifies putative regulatory roles for unstudied TFs.
    • Thumbnail

      The genome-wide multi-layered architecture of chromosome pairing in early Drosophila embryos

      Erceg, Jelena; AlHaj Abed, Jumana; Goloborodko, Anton; Lajoie, Bryan R.; Fudenberg, Geoffrey; Abdennur, Nezar; Imakaev, Maxim; McCole, Ruth B.; Nguyen, Son C.; Saylor, Wren; et al. (2019-10-03)
      Genome organization involves cis and trans chromosomal interactions, both implicated in gene regulation, development, and disease. Here, we focus on trans interactions in Drosophila, where homologous chromosomes are paired in somatic cells from embryogenesis through adulthood. We first address long-standing questions regarding the structure of embryonic homolog pairing and, to this end, develop a haplotype-resolved Hi-C approach to minimize homolog misassignment and thus robustly distinguish trans-homolog from cis contacts. This computational approach, which we call Ohm, reveals pairing to be surprisingly structured genome-wide, with trans-homolog domains, compartments, and interaction peaks, many coinciding with analogous cis features. We also find a significant genome-wide correlation between pairing, transcription during zygotic genome activation, and binding of the pioneer factor Zelda. Our findings reveal a complex, highly structured organization underlying homolog pairing, first discovered a century ago in Drosophila. Finally, we demonstrate the versatility of our haplotype-resolved approach by applying it to mammalian embryos.
    • Thumbnail

      Determination of ubiquitin fitness landscapes under different chemical stresses in a classroom setting

      Mavor, David; Roscoe, Benjamin P.; Bolon, Daniel N.; Fraser, James S. (2016-04-25)
      Ubiquitin is essential for eukaryotic life and varies in only 3 amino acid positions between yeast and humans. However, recent deep sequencing studies indicate that ubiquitin is highly tolerant to single mutations. We hypothesized that this tolerance would be reduced by chemically induced physiologic perturbations. To test this hypothesis, a class of first year UCSF graduate students employed deep mutational scanning to determine the fitness landscape of all possible single residue mutations in the presence of five different small molecule perturbations. These perturbations uncover 'shared sensitized positions' localized to areas around the hydrophobic patch and the C-terminus. In addition, we identified perturbation specific effects such as a sensitization of His68 in HU and a tolerance to mutation at Lys63 in DTT. Our data show how chemical stresses can reduce buffering effects in the ubiquitin proteasome system. Finally, this study demonstrates the potential of lab-based interdisciplinary graduate curriculum.
    DSpace software (copyright © 2002 - 2023)  DuraSpace
    Lamar Soutter Library, UMass Chan Medical School | 55 Lake Avenue North | Worcester, MA 01655 USA
    Quick Guide | escholarship@umassmed.edu
    Works found in eScholarship@UMassChan are protected by copyright unless otherwise indicated.
    Open Repository is a service operated by 
    Atmire NV
     

    Export search results

    The export option will allow you to export the current search results of the entered query to a file. Different formats are available for download. To export the items, click on the button corresponding with the preferred download format.

    By default, clicking on the export buttons will result in a download of the allowed maximum amount of items.

    To select a subset of the search results, click "Selective Export" button and make a selection of the items you want to export. The amount of items that can be exported at once is similarly restricted as the full export.

    After making a selection, click one of the export format buttons. The amount of items that will be exported is indicated in the bubble next to export format.